Granulation Processes Flashcards
1
Q
What is granulation?
A
- size enlargement process for the capsules that involves binder liquid.
- original constituents can still be identified even with the physical change.
2
Q
What are the advantages of granulation?
A
- improve flowability
- reduce segregation tendency
- improve compactibility
- reduce dust
3
Q
What are the different methods of granulation?
A
- direct compression
- dry granulation
- thermoplastic granulation
- wet granulation
4
Q
What are the characteristics of direct compression?
A
- sometimes referred to as dry granulation
- suitable for preparing free flowing powders for tableting
- involves mixing and blending without the need to increase particle size
- minimal segregation and good compressibility
5
Q
What are the characteristics of dry granulation?
A
- also known as slugging
- used to compress pre-mix into large tablets or slugs (25mm or larger), which are poor quality tablets
6
Q
What is a common technique used for dry granulation, and how does it work?
A
roller compaction (capable of continuous production)
- Homogeneously mixed powder blend is passed between two counter-rotating rollers.
- Compact is formed, and can be milled into granules.
7
Q
What are some advantages of roller compaction?
A
- fewer unit processes required thus lower production cost
- suitable for heat and/or water-sensitive materials
- feasible process for preparing controlled release products
8
Q
What are some of the bonding mechanisms in dry graulations?
A
- particle rearrangement
- particle fragmentation
- particle bonding
9
Q
What are some factors affecting compact strength?
A
- applied pressure
- extent of air entrapment (improve process by vacuum system)
- roll dwell time
- powder void fraction (space into which air is compacted)
- particle size of component and density
- type of binders included
- moisture content of material
10
Q
What are the characteristics of wet granulation?
A
- most widely used technique
- possible for almost any powder or mixture of powders provided that are stable to moisture and heat.
- hardness and solubility can be controlled with the appropriate binders and granulating agents.
- non-aqueous agents can be used for water sensitive materials.
11
Q
What are the advantages of wet granulation?
A
- improve flow properties
- reduce bulk volume, densification
- improve compression properties
- improve distribution of a minor constituent (e.g. low dose drug, binder, colorant)
- prevent components from segregating
- reduce dust
- minimise or mitigate adverse effects of API
12
Q
What are the disadvantages of wet granulation?
A
- additional processing steps, more tedious and adds cost
- unsuitable for moisture-sensitive or thermolabile drugs
- material loss due to additional processing steps
13
Q
What are the steps for wet granulation (small scale)?
A
- Addition of granulating liquid to API and excipients generates a moistened mass.
- Moistened mass passes through screen to form exudates
- Exudates are dried at 60 degree celsius to form dried exudates
- Dried exudates are re-granulated through screen to give granules and lubricant.
- Granules and lubricant are compacted to form tablets
14
Q
Describe agglomerate growth.
A
- happens during wet granulation process with agitation, when an equilibrium exists between crushing and coalescence.
- if the equilibrium favours the coalescence mechanism, the agglomerate grows.
15
Q
Describe liquid saturation.
A
- liquid saturation refers to the ratio of the pore volume occured by the liquid : total volume of pores within the agglomerate.
- unsaturated, 3-phase system: air, liquid and solid
- saturated, 2-phase system: liquid and solid
16
Q
What are the states and effects of densification?
A
States ( in increasing order of saturation):
pendular –> funicular –> capillary –> droplet
- can be caused by liquid addition and densification
- densification increases liquid saturation and surface plasticity, promoting agglomeration growth.
- as density increases, agglomerate becomes more resistant to breakdown.
17
Q
What are the differences, energy input and liquid addition wise between high shear granulation and fluid bed granulation?
A
high shear granulation – as more liquid is added, energy input increases proportionally.
fluid bed granulation – as more liquid is added, energy input remains the same (not responsive to change in liquid volume)
18
Q
How does the particle size of primary components influence granulation?
A
- smaller particles require higher amount of binder liquid than larger ones because they are more difficult to densify (higher packing density).
- total primary particles’ surface area is larger for smaller particles than larger ones, assuming agglomerate size is kept constant.
19
Q
How does particle shape influence granulation?
A
- particle shape affects the packing properties of the materials
- irregular particle shape interlocks particles and increases the agglomerate strength and the packing ability of the agglomerate.
- rounder particles reduce particle packing abilities.
20
Q
How does size and size distribution of granules affect granulation?
A
High agglomerate strength if:
- particles are on average small in size
- have wide size distribution
- processes involved: nucleation and coalescence
Low agglomerate strength if:
- particles are on average large in size
- have narrow size distribution
- processes involved: nucleation and layering
21
Q
What is the final fate of granules in wet granulation?
A
For hydrophobic drugs:
- binder is required
- when dried, results in the formation of solid bridges and agglomeration.
For hydrophilic drugs:
- binder liquid not required
- particles do not form solid bridges and exist as individual particles.
22
Q
What are the bonding mechanisms used in agglomeration?
A
- Adhesion and cohesion forces by immobile liquid film. Used for secondary bonding mechanisms.
» attractive forces (van der Waals, ionic, electrostatic) that form interlocking bonds to hold particles together. - Interfacial forces and capillary pressure of mobile liquid, prerequisite to solid bridges
- Solid bridges
23
Q
What are the different agglomerate growth mechanisms?
A
- nucleation
» start of granulation, primary particles are drawn to form 3-phase particle. - coalescence
» formation of larger agglomerates by successful collisions. - layering
» successive addition of fines on larger agglomerates. - abrasion transfer
» mass transfer between two colliding agglomerates, resulting in material from one agglomerate deposited onto another. - Ball growth
» rapid growth into large, spherical granules
24
Q
What are the characteristics of high shear mixer (HSM) granulator?
A
- widely used as mixer and granulator
- blending and wet massing
» strong mechanical agitation by an impeller
» de-lumping by a chopper - mixing, densification and agglomeration of wetter materials
» sharing and compaction forces exerted by the impeller
» tip speed about 5-15m/s - lumps are broken into smaller fragments
» chopper is a small agitator that is run at a high rotational speed
25
What are the different configurations of HSM?
- top-drive
- bottom-drive
- bottom-drive for impeller, top-drive for chopper
26
What are the process steps for granulation by HSM?
1. mixing of dry powder at high impeller speeds (2-5 mins)
2. addition of liquid binders at lower speeds (1-2 min)
3. wet massing at high speeds (1-5 min)
4. wet sieving of granules with cone mill
5. drying with the fluid bed dryer
6. re-granulation by cone mill
27
What are the advantages of HSM granulation?
- short process time
- less binder needed, therefore shorter drying time
- suitable for cohesive materials and dense products
28
What are the problems associated with HSM granulation?
- mechanical degradation of weak powders and granules
- some heat generation, unsuitable for thermolabile products
- risk of over-wetting, leading to uncontrolled growth
29
What are the process variables used?
- impeller rotation speed (tip speed)
- chopper rotation speed
- load
- liquid addition method
- liquid addition rate
- wet massing time
30
Chopper size and rotation speed affect granulation size distribution (T/F)?
- Chopper size and rotation speed have no effect upon the granule size distribution.
- Primary function of the chopper is to disturb the uniform flow pattern of the mass, and chop up oversized aggregates.
31
Describe the theory of fluidisation.
- In fluidisation, air is passed through the material bed fast enough so that it sets the particles in motion, but does not cause the particles to reach terminal velocity. This is accompanied by a drop in pressure across the material bed.
32
During batch fluid bed processing, air moves through the product layers for:
1. granulation
2. drying
3. coating
33
What affects granule formation and growth?
- choice of binder, concentration and viscosity
34
What are the different mechanisms of granulation in fluid bed?
-droplet formation
-evaporation
-sticky droplets contact powder particles
-open lattice 'snowflake' type granule
>> good binder distribution
>> good compressibility
35
What are the characteristics of fluid bed granules?
- open structure
- bulk density similar to raw materials
- good distribution of binder on surface
- uniform and narrow particle size distribution
- good texture
36
What is hot melt extruder and how does it help with thermoplastic granulation?
Hot melt extrusion is the process of applying heat and pressure to melt the polymer, and continuously forcing it through the orifice to make extrudates.
Polymers are melted so that they can be incorporated with APIs to enhance the bioavailability and solubility of poorly water soluble APIs.
37
What are the components involved in hot melt extrusion?
- feeder for material entry
- heat-jacketed barrel with one or two rotating screws where the melting and granulation occur
- orifice for shaping the material before it leaves the extruder
- downstream auxiliary equipment for cooling, cutting and collecting the finished product.
38
What is another alternative technology for thermoplastic extrusion?
- granulation by twin screw extrusion
